Process for synthesizing cationic lipids

Abstract

The present application provides processes for synthesizing cationic lipids of Formula I useful in the synthesis of fat-soluble compositions for targeting and enhancing activity of therapeutic molecules, including siRNA.

What is claimed is: 
     
         1 . A process for synthesizing a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein a is an integer from 8-14; 
         b is an integer from 1-3; and 
         Z is Br; 
         the process comprising,
 a) reacting a compound of Formula II 
 
       
       
         
           
           
               
               
           
         
         wherein R is a protecting group; 
         with a compound of Formula III 
       
       
         
           
           
               
               
           
         
         wherein X is a halogen; 
         and methanesulfonic acid 
         to form a compound of Formula IV 
       
       
         
           
           
               
               
           
         
         b) reacting a compound of Formula IV with a compound of Formula V 
       
       
         
           
           
               
               
           
         
         and oxalic acid to form a compound of Formula VI 
       
       
         
           
           
               
               
           
         
         and
 c) reacting a compound of Formula VI with bromoethanol under coupling conditions to form a compound of Formula I. 
 
       
     
     
         2 . The process of  claim 1  wherein a is 12. 
     
     
         3 . The process of  claim 1  wherein b is 2. 
     
     
         4 . The process of  claim 1  wherein R is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, tosyl, trichloroethyl chloroformate, (4-nitrophenyl) sulfonyl, methyl, ethyl, propyl, n-butyl, t-butyl, succinimide, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoroethyl, phenyl, and 4-methoxybenzyl. 
     
     
         5 . The process of  claim 4  wherein R is t-butyloxycarbonyl. 
     
     
         6 . The process of  claim 1  wherein X is Cl or Br. 
     
     
         7 . The process of  claim 6  wherein X is Cl. 
     
     
         8 . The process of  claim 1  wherein the yield of step a) is at least about 80%. 
     
     
         9 . The process of  claim 1  wherein the yield of step b) is at least about 80%. 
     
     
         10 . The process of  claim 1  wherein in step c) bromoethanol is used in between about 2 and about 4 equivalents and the compound of Formula VI is used in about 1 equivalent. 
     
     
         11 . The process of  claim 10  wherein in step c) bromoethanol is used in about 2.2 equivalents. 
     
     
         12 . The process of  claim 1  wherein the compound of Formula IV is isolated as a solid. 
     
     
         13 . The process of  claim 12  wherein the compound of Formula IV is isolated as a crystalline solid. 
     
     
         14 . The process of  claim 1  wherein the compound of Formula VI is isolated as a crystalline solid. 
     
     
         15 . The process of  claim 1  wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The process of  claim 1  wherein the compound of Formula I is produced in at least about 60% yield from the compound of Formula II.